It has been pointed out that substances and compounds reported to have an antitumor activity based only on in vitro data alone generally do not allow anticipation of their effects in the in vivo results. In other words, a substance showing an antitumor activity in vitro does not necessarily show an antitumor activity also in vivo, and therefore, the application of a substance showing an antitumor activity in vitro directly as an anti-cancer agent is problematic.
For example, it has been reported that a compound (Sequence Listing SEQ ID NO. 1) of the formula (I)
induces a strong antitumor activity by selectively inhibiting histone deacetylase. It has been also reported that this substance causes high acetylation of histone in the cells treated with this substance, and as a result, induces a transcription controlling activity of various genes, a cell cycle inhibitory activity and an apoptosis inhibitory activity (JP-B-7-64872, H. Nakajima et al., Exp. Cell Res. 241, 126-133 (1998)). As the situation stands, however, there are many problems yet to be solved, such as effectiveness of in vitro results in in vivo application, in vivo effectiveness against any tumor and the like. The antitumor activity in vitro against kidney cancer has been reported, but an antitumor activity in vivo against kidney cancer has not been reported.
Histone deacetylase is a metallo deacetylase having Zn coordinated at the active center (M. S. Finnin et al., Nature, 401, 188-193 (1999)). This enzyme is considered to change affinity of various acetylated histones for DNA. The direct biological phenomenon provided thereby is a change in the chromatin structure. The minimum unit of the chromatin structure is a nucleosome wherein a 146 bp DNA winds around a histone octamer (H2A, H2B, H3 and H4, 2 molecules each, core histone) 1.8 times counterclockwise. The core histone stabilizes the nucleosome structure as the positive charge of the N-terminal of each histone protein interacts with DNA. The acetylation of histone is controlled by the equilibrium relationship between acetylation reaction, in which histone acetyltransferase is involved, and the deacetylation reaction, in which histone deacetylase is involved. The acetylation of histone occurs in an evolutionarily well-conserved lysin residue in the N-terminal of a histone protein, whereby, it is considered, the core histone protein loses the charge of the N-terminal, the interaction with DNA decreases, and the structure of nucleosome is instabilized. Conversely, therefore, deacetylation of histone is considered to stabilize the nucleosome structure. However, the degree of changes in the chromatin structure caused by the acetylation is unclear nor is it clear how it is related to the secondarily induced control of transcription.